The high thermodynamic and kinetic stability of chelates formed between lanthanide(III) cations and polyazamacrocyclic ligands having pendent acetate (Desreux et al.; Stetter et al.; Hama et al.; Cortes et al.), phosphonate (Geraldes et al. (Inorg. Chem.); Polikarpou et al.; Delgado et al.), phosphonate monoester, and phosphinate side-chains have lead to considerable interest in their use as NMR shift reagents in biological systems or as magnetic resonance imaging (MRI) contrast agents (Lauffer). A new application for the tri- and tetraaza macrocycle derivatives having phosphorous-containing pendent groups is for noninvasive in vivo monitoring of intracellular concentrations of free Ca(II), Mg(II), and Zn(II) by .sup.31 P NMR (Ramasamy et al.).
In most cases, this application will require fine tuning of the binding constant under physiological conditions for a particular metal ion, keeping it in the same range as the free metal ion concentration in the cell, to achieve the desired equal concentrations of free ligand and metal ion complex.
One method of fine tuning is to introduce two or more different pendent groups onto the macrocycle, but the synthesis of polyazamacrocycles with specific numbers of even a single pendent N-substituent group (acetic acid, for example) has proven difficult with prior art methods (Neves et al.; Tweedle et al.; Kruper; Dischino et al; Studer et al.). Yields of diacetic acid derivatives prepared as in the prior art, with specified pendent group distributions, have been poor. Such conventional synthetic methods produce mixtures of the desired product with macrocycles having different pendent group distributions, thus necessitating subsequent separation of the desired species.